Project Summary: The overall goal is to elucidate and mitigate mechanisms of maladaptive metabolic remodeling that may contribute to cardiac dysfunction and the progression to decompensated cardiac hypertrophy. The proposal originates from novel findings in our laboratory: 1) that stored triglyceride (TG) in the heart is quite dynamic, but TG turnover is slow in failing hearts as is TG content, the latter being confirmed in heart failure patients without diabetes. The loss of TG turnover reduces the contribution of long chain fatty acids (LCFA) from TG to fatty acid oxidation (FAO) and impairs TG lipolytic activation of PPAR?. We have reported that while palmitate sustains this reduced TG metabolism and PPAR? activation in hypertrophied hearts, oleate normalizes each of these very same parameters; 2) Our lab first reported increased protein content of the liver isoform of the rate limiting enzyme in FAO, carnitine palmitoyltransferase I (CPT1) in hypertrophied hearts. We also found acute expression of the liver CPT1 (CPT1a) in healthy hearts induced two surprising results; a paradoxical reduction in FAO and elevated myocardial atrial natriuretic peptide mRNA, both classically observed responses to [ pathogenic stress. 3) Preliminary data show isoform specific acylation and responses to TAC. 4) CPT1a expression is suppressed by Mir-370 and that Mir370 content is low in hypertrophied hearts. Thus, we hypothesize that: 1) Supplying an oleate rich diet provides benefits to rat hearts following transverse aortic constriction (TAC) by a) maintaining TG turnover and PPAR? target gene expression, b) influencing the formation of ceramide species, and c) thereby attenuating dysfunction and decompensation. 2) Increased CPT1a in hypertrophied hearts is a key step in the early metabolic remodeling that influences cardiac decompensation and is linked to hypertrophic signaling. 3) Increased CPT1a in hypertrophied hearts is linked to reduced FAO via changes in isoform-specific, CPT1 acetylation and malonylation, and these changes respond to CPT1a regulation via restored Mir-370. Aim 1 a) determines effects of palmitate- (tripalmitin) ] versus oleate-rich (triolein) diets on decompensation after TAC in rat hearts, and b) determines if triolein and tripalmitin diets post-TAC affect TG turnover, PPAR? target gene expression, LCFA oxidation and lipotoxic acyl-intermediates. Aim 2 determines the role of the isoform shift to CPT1a (liver) expression in the reduced LCFA oxidation and progression toward decompensation and early HF. Cardiac specific, CPT1a null mice, that [ are unable increase CPT1a in response to TAC, will be examined for functional and hypertrophic responses to TAC. The potential for altered FAO through exclusive changes in CPT1b isoform content and acylation, will be elucidated in the restricted absence of a CPT1a response. Aim 3 elucidates potentially maladaptive ] upregulation of CPT1a, due to reduced Mir-370 during TAC, and the role of CPT1a expression in acetylation and malonylation of both CPT1 isoforms. Low Mir-370 following TAC in rat hearts will be countered by acutely overexpressing Mir-370 to suppress CPT1a and downstream effects.